CN1233174A - Naringin and naringenin as 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitor - Google Patents
Naringin and naringenin as 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitor Download PDFInfo
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- CN1233174A CN1233174A CN97198802A CN97198802A CN1233174A CN 1233174 A CN1233174 A CN 1233174A CN 97198802 A CN97198802 A CN 97198802A CN 97198802 A CN97198802 A CN 97198802A CN 1233174 A CN1233174 A CN 1233174A
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- naringin
- naringenin
- coa
- hmg
- hydroxy
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- 229930003231 vitamin Natural products 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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Abstract
A pharmaceutical composition for inhibiting the activity of 3-hydroxy-3-methylglutaryl CoA(HMG-CoA) reductase in mammals comprises an effective amount of naringin or naringenin as an active ingredient together with a pharmaceutically acceptable carrier, and a food or beverage composition for inhibiting the 3-hydroxy-3-methylglutaryl CoA(HMG-CoA) reductase activity in mammals comprises an effective amount of naringin or naringenin.
Description
Invention field
The present invention relates to suppress the pharmaceutical composition of 3-hydroxy-3-methylglutaryl-coenzyme A in the mammal (HMG-CoA) reductase activity, said composition comprise effective dose as acceptable carrier on the naringin of active component or naringenin and the materia medica, the invention still further relates to the Foods or drinks compositions that is used to suppress the HMG-CoA reductase activity, said composition comprises the naringin or the naringenin of effective dose.
Background of invention
In the last few years, crown cardiovascular circulation disease, for example atherosclerosis and hypercholesterolemia become the main cause of death gradually.Existing reporting, plasma cholesterol concentration are increased and are caused fat, macrophage and foam cell to be deposited on the blood vessel wall, and these depositions then cause speckle to form, and cause atherosclerosis (Ross, R., Nature, 362,801-809 (1993)) thus.One of method that reduces plasma cholesterol concentration is a diet material method, with the absorption of cholesterol reducing and lipid.Another kind method is the biosynthesis speed that is reduced in the cholesterol that carries out in the liver.Existing reporting, hypercholesterolemia can by suppress the HMG-CoA reductase and thus the biosynthesis speed of cholesterol reducing treat effectively, described HMG-CoA reductase mediation 3, synthesizing of 5-dihydroxy-3 methylvaleric acid, this chemical compound is intermediate (Cardiovascular Pharmacology, William W.Parmley and Kanu Chatterjee Ed., the Wolfe Publishing in the biosynthesis of sterol or isoprenoid, pages8.6-8.7,1994).
Therefore, carry out many effort and developed the medicine that can suppress the HMG-CoA reductase; Consequently existing several chemical compound that obtains from Penicillium sp. and Aspergillus sp. comes into the market to sell.Particularly, Merck Co., Lovastatin and the Simvastatin and the Sankyo Co. of USA development, the Pravastatin of Japan development has sold (C.D.R.Dunn on market, Stroke:Trends, Treatment and Markets, SCRIPT Report, PJB Publications Ltd., 1995).But these medicines are very expensive, and the side effect that creatine kinase increases in the liver is brought out in known long term administration meeting.Therefore, still be necessary to continue the cheap and avirulent HMG-CoA reductase inhibitor of development.
The aglycone of naringin and naringin--naringenin is the flavones of finding in Fructus Citri Limoniae, grapefruit, mandarin orange and orange (Fructus Citri sinensis, Citrus sinensis), and they have following structure (Horowitz, Gentili, Tetrahedron, 19,773 (1963)):
Naringin has been used as bitters, stimulant (sweater) or chewing gum base.But, do not report that still naringin or naringenin have the activity of HMG-CoA reductase inhibitor.
The invention summary
Therefore, the purpose of this invention is to provide a kind of pharmaceutical composition that is used for suppressing mammal HMG-CoA reductase activity.
Another object of the present invention provides a kind of Foods or drinks compositions that is used for suppressing mammal HMG-CoA reductase activity.
According to an aspect of the present invention, it provides a kind of active pharmaceutical composition that is used for suppressing mammal 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, said composition comprise effective dose as acceptable carrier on the naringin of active component or naringenin and the materia medica.Detailed Description Of The Invention
The invention provides a kind of pharmaceutical composition that is used to suppress the HMG-CoA reductase activity, said composition comprises as acceptable excipient, carrier or diluent on the naringin of active component or naringenin and the materia medica.
Naringin and naringenin can extract from the skin of orange, and perhaps according to Rosenmund (Rosenmund, Ber., 61,2608 (1958)) and Zemplen, the method that Bognar (Ber., 75,648 (1942)) describes is synthesized.Naringenin then can prepare by the hydrolysis naringin.
Naringin or naringenin are inhibited to the HMG-CoA reductase when 0.05mg/kg/ days or higher dosage, and this inhibitory action increases with dosage.
And although strong effectiveness is arranged, naringin and naringenin almost do not show toxicity or mitogenesis in the Mus experiment.More specifically, when giving the Mus oral administration with the dosage of 1000mg/kg, naringin does not have toxigenicity, and for the heavy people of 50kg, above-mentioned dosage is equivalent to oral administration 50-100g naringin/kg body weight.In addition, naringin and naringenin are free from side effects to liver function.
Can use above-mentioned composition to come useful in preparing drug formulations according to any conventional method.During preparation, naringin or naringenin preferably mix with carrier or dilute with carrier in preparation, perhaps are encapsulated in the carrier of form of capsule, sachet or other containers.If carrier is a diluent, it can be solid, semisolid or liquid substance, as carrier, excipient or the medium of active component.Therefore, preparation can be the dosage forms such as powder of tablet, pill, powder, sachets, elixir, suspensoid, Emulsion, solution, syrup, aerosol, soft hard gelatin capsule, aseptic parenteral solution, aseptic packaging.
The example of suitable carriers, excipient and diluent is lactose, glucose, sucrose, sorbitol, mannitol, starch, Radix Acaciae senegalis, alginate, gelatin, calcium phosphate, calcium silicates, cellulose, methylcellulose, microcrystalline Cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, nipasol, Pulvis Talci, magnesium stearate and mineral oil.Pharmaceutical preparation can comprise filler, anti-agglomerant, lubricant, wetting agent, flavoring agent, emulsifying agent, antiseptic etc. in addition.Compositions of the present invention can be mixed with the preparation of quick after delivering medicine to mammal, lasting or delayed release of active elements with any methods known in the art.
Pharmaceutical preparation of the present invention administration by all means comprises oral, transdermal, subcutaneous, vein and muscle administration.For the people, the typical daily dose of naringin or naringenin is about 0.05-300mg/kg body weight, is preferably 0.5-30mg/kg, and this dosage can single dose or the administration of many doses.It should be understood that the amount of the active component of actual administration should determine that described factor comprises the order of severity of disease to be treated, selected route of administration, each patient's age, sex and body weight and patient's symptom according to various correlative factors; Therefore, above-mentioned dosage never is to be used to limit the scope of the invention.
In addition, naringin and naringenin can be incorporated in the Foods or drinks, are used to suppress the HMG-CoA reductase activity.Therefore, the present invention also is provided for suppressing the Foods or drinks compositions of HMG-CoA reductase activity, and said composition comprises the naringin or the naringenin of effective dose.
As mentioned above, naringin or naringenin can be used as the non-drug toxicity of effective inhibition HMG-CoA reductase activity.
Following examples are used for further illustrating the present invention, rather than limit its scope.
In addition, the solid percentage ratio in the solid in the following solid mixture, the liquid in the liquid and the liquid is respectively to calculate with wt/wt, vol/vol and wt/vol, and all reactions all are at room temperature to carry out, except as otherwise noted.Embodiment 1: to animals administer naringin and naringenin
With body weight be at random 30 4 of 90-110g age in week the Sprague-Dawley mice (Taihanlaboratory animal center Korea) is divided into 3 groups.The mice of three groups is fed with three kinds of different high-cholesterol diet respectively, AIN-76 laboratory animal feedstuff (the ICN Biochemicals that promptly comprises 1% cholesterol, Cleveland, OH, USA) (matched group), 1% cholesterol add 0.1% naringin (naringin group) and 1% cholesterol adds 0.1% naringenin (naringenin group).Three the feeds utilized compositions of group I that see the following form.
The table I
*1: (Madison, WI USA) buy from TEKLAD Premier Co.
*2: available from Sigma Chemical Company (St.Louis, MO, USA)
| Feed ingredient | Matched group | The naringin group | The naringenin group |
| Casein | ??????20 | ???????20 | ????20 |
| D, the L-methionine | ?????0.3 | ??????0.3 | ???0.3 |
| Corn starch | ??????15 | ???????15 | ????15 |
| Sucrose | ??????49 | ??????48.9 | ???48.9 |
| Cellulose powder *1 | ??????5 | ???????5 | ????5 |
| Mineral mixture *1 | ?????3.5 | ??????3.5 | ???3.5 |
| Vitamin mixtures *1 | ??????1 | ???????1 | ????1 |
| Choline citrate | ?????0.2 | ??????0.2 | ???0.2 |
| Semen Maydis oil | ??????5 | ???????5 | ????5 |
| Cholesterol | ??????1 | ???????1 | ????1 |
| Naringin *2 | ??????0.1 | ||
| Naringenin *2 | ???0.1 | ||
| Amount to | ????100 | ??????100 | ???100 |
Unrestrictedly apparatus body feedstuff and water are fed mice totally 6 weeks, write down intake every day, weighed in per then 7 days, and the analytic record data.All mices all show the normal speed of growth, and are not having significant difference aspect food intake and the weight increase between three groups.Embodiment 2: T-CHOL, HDL-cholesterol and neutral lipid Determination on content in the blood plasma
Below measure to the influence of mice administration naringin and naringenin plasma cholesterol and neutral lipid content.
From the mice of last three groups, take blood sample, and with the HDL-cholesterol reagent that comprises glucose sulfuric ester (Sigma Chemical Co., Cat.No.352-2) separated plasma HDL composition therefrom.(Sigma Chemical Co. USA) measures T-CHOL and HDL-cholesterol concentration (Allain et al., Clin.Chem., 20,470-475 (1974)) with Sigma Diagnostic Kit Cat.No.352-100.(SigmaChemical Co. USA) measures neutral lipid concentration (Bucolo, G.And David, H., Clin.Chem., 19,476-482 (1973)) with Sigma Diagnostic Kit Cat.No.339-50.The results are shown in Table II, wherein, compare, the total plasma cholesterol lowering of concentration 32% of mice in the naringin raising group, and the total plasma cholesterol lowering of concentration 18% of mice in the naringenin raising group with control group mice.
The table II
*Always-and C: total-cholesterol
*The HDL-C:HDL-cholesterol
*TG: triglyceride embodiment 3: (step 1) prepares microsome to naringin and the naringenin activity in HMG-CoA suppresses
| Group | Matched group | The naringin group | The naringenin group |
| Always-C (mg/dl) | 147.8±34.8 | ??100.8±16.1 | ???120.9±25.9 |
| HDL-C(mg/dl) | ????22.2 | ??????24.0 | ???????23.4 |
| HDL-C/ is total-C (%) | ?15.7±5.3 | ????23.9±7.6 | ?????20.8±9.1 |
| TG(mg/dl) | ?99.2±18.9 | ???86.7±14.6 | ???103.4±18.2 |
For determining to raise the effect of mice to the HMG-CoA reductase activity with naringin and naringenin, the preparation microsome is as the enzyme source from hepatic tissue, and described reductase is a biosynthetic enzyme of regulating cholesterol in the liver.
At first, with above-mentioned three groups of mice sacrificed by decapitation, take out liver, and be placed on ice-cooled homogenate medium (50mM KH immediately
2PO
4(pH7.0), 0.2M sucrose, 2mM dithiothreitol, DTT (DTT)) in.In homogenate medium (2ml medium/g liver), made liver homogenate 15 seconds with Waring blender (the Potter-Elvehjem type glass homogenizer of three strokes has the Teflon pestle that a motor drives).Centrifugal homogenate is 10 minutes under 15000 * g, and the supernatant that obtains thus under 100000 * g centrifugal 75 minutes obtains the microsome precipitation, will precipitate to be suspended in again in the homogenate medium that comprises 50mM EDTA under 100000 * g centrifugal 60 minutes then then.With comprising MC supernatant as the enzyme source.The experiment of (step 2) HMG-CoA reductase
Following method according to people such as Shapiro (Biochemical et Biophysica Acta, 370,369-377 (1974)) use [
14C] HMG-CoA measures the activity of HMG-CoA reductase.
37 ℃ down activation contain enzyme 30 minutes in the clear liquid on the microsome (obtaining in the step 1).The HMG-CoA reductase experiment buffer (0.25MKH that in reaction tube, adds 20 μ l
2PO
4(pH7.0), 8.75mM EDTA, 25mM DTT, 0.45M KCl and 0.25mg/mlBSA), 50mM NADPH, the 5 μ l of 5 μ l [
14C] the activated microsomal enzyme (0.03-0.04mg) of HMG-CoA (0.05 μ Ci/ test tube, ultimate density 120 μ M) and 10 μ l, mixture was cultivated these mixture 30 minutes down at 37 ℃ then.The 6M hydrochloric acid that adds 10 μ l in this mixture makes reaction stop thus, cultivates this mixture 15 minutes down at 37 ℃ then, and product (mevalonic acid) is lactonized fully.Under 10000 * g centrifugal 1 minute, disgorging thus, then supernatant is used in silica gel 60G TLC plate (Altech, Inc., Newark, USA) on, and use benzene: acetone (1: 1, v/v) launch.Scrape the zone of Rf value between 0.65-0.75 with disposable microscope slide, and (Wallacoy Finland) carries out the radioactivity experiment with the 1450Microbeta liquid scintillation counter.With the synthetic mevalonic acid of pmol/minute/mg albumen calculates enzymatic activity.The results are shown in Table III.The table III
| Group | Matched group | The naringin group | The naringenin group |
| HMG-CoA reductase activity (pmol/min/mg albumen) | 147±12.5 | ?111.1±14 | ?101.4±7.3 |
From the table III the result as can be seen, control group mice has relative higher H MG-CoA reductase activity, observed HMG-CoA activity then is lower than matched group 25% and 31% respectively in naringin raising group and the naringenin raising group mice.Embodiment 4: the toxicity of oral administration naringin
Under the condition of 22 ± 1 ℃ temperature, 55 ± 5% humidity and periodicity of illumination 12L/12D, raise the female Mus of ICR (8) and the male Mus (8) of 7-8 age in week, specific pathogen free, female Mus weight is at 25-29g, and male Mus weight is at 34-38g.With feedstuff (Cheiljedang Co., Mus feedstuff) and water sterilization, feed to mice then.
Naringin is dissolved among the 0.5%Tween80, to concentration be 100mg/ml, then this solution is administered orally to mice, consumption is a 0.2ml/20g mice body weight.Behind the described solution of administration, observe mice 10 days and write down side effect or the phenomena of mortality: after the administration 1,4,8 and 12 hour, then observed later on every 12 hours by following program.Write down the mice body weight change every day, to check the effect of naringin.In addition, in the time of the 10th day, mice is put to death, and the macroscopy internal.
All mices all survive in the time of the 10th day, and the naringin of 1000mg/kg dosage does not have toxicity.The postmortem result is, mice does not form the improper property of any pathology, and do not observe during 10 days inspection and lose weight.Therefore, can draw to draw a conclusion: naringin does not have toxicity when the oral administration animal.
Following example of formulations only is used to illustrate the present invention, and never limits the scope of the invention.Example of formulations
Use following composition to prepare hard gelatin capsule:
Amount (mg/ capsule) active component (naringin) 20 dry starch 160 magnesium stearate 20 amount to 200mg
Though invention has been described with reference to above-mentioned specific embodiments, it should be understood that those skilled in the art also can carry out various improvement and variation within the scope of the invention, and scope of the present invention limited by following claims.
Claims (6)
1, a kind of pharmaceutical composition that is used for suppressing mammal 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity, it comprise effective dose as acceptable carrier on the naringin of active component or naringenin and the materia medica.
2, pharmaceutical composition as claimed in claim 1, wherein, described mammal is the people.
3, pharmaceutical composition as claimed in claim 2, wherein, the effective dose of naringin is the 0.05-300mg/kg body weight/day.
4, pharmaceutical composition as claimed in claim 2, wherein, the effective dose of naringenin is the 0.05-300mg/kg body weight/day.
5, a kind of food compositions that is used for suppressing mammal 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity, it comprises the naringin or the naringenin of effective dose.
6, a kind of beverage composition for treating dental erosion that is used for suppressing mammal 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity, it comprises the naringin or the naringenin of effective dose.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR45735/1996 | 1996-10-14 | ||
| KR1019960045735A KR100213895B1 (en) | 1996-10-14 | 1996-10-14 | Compositions for the prevention and therapy of cardiovascular disease containing extract of citrus fruit peel hesperidin or naringin |
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| CN1233174A true CN1233174A (en) | 1999-10-27 |
| CN1106840C CN1106840C (en) | 2003-04-30 |
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| CN97198801A Pending CN1233182A (en) | 1996-10-14 | 1997-10-13 | Citrus peel extract as 3-hydroxy-3-methyl glutaryl-CoA (HMG-CoA) reductase inhibitor |
| CN97198802A Expired - Fee Related CN1106840C (en) | 1996-10-14 | 1997-10-13 | Naringin and naringenin as 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitor |
| CN97198803A Expired - Fee Related CN1104897C (en) | 1996-10-14 | 1997-10-13 | Hesperidin and hesperetin as 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitor |
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| CN97198801A Pending CN1233182A (en) | 1996-10-14 | 1997-10-13 | Citrus peel extract as 3-hydroxy-3-methyl glutaryl-CoA (HMG-CoA) reductase inhibitor |
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| CN97198803A Expired - Fee Related CN1104897C (en) | 1996-10-14 | 1997-10-13 | Hesperidin and hesperetin as 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase inhibitor |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103304610A (en) * | 2012-12-24 | 2013-09-18 | 李玉山 | Preparation process of methyl hesperidin |
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| US6239114B1 (en) * | 1997-09-26 | 2001-05-29 | Kgk Synergize | Compositions and methods for treatment of neoplastic diseases with combinations of limonoids, flavonoids and tocotrienols |
| CN1124134C (en) * | 1997-10-28 | 2003-10-15 | 韩国科学技术研究院 | Naringin and naringenin as inhibitor of acyl coa-cholesterol-o-acyltransferase, ihibitor of macrophage-lipid complex accumulation on the arterial wall and preventive agent |
| WO2000023073A1 (en) * | 1998-10-20 | 2000-04-27 | Korea Institute Of Science And Technology | Bioflavonoids as plasma high density lipoprotein level increasing agent |
| JP2002535410A (en) * | 1999-01-27 | 2002-10-22 | ザィエリンスキ，ラブラトリー | Hesperetin proform with enhanced bioavailability |
| US6123968A (en) * | 1999-03-23 | 2000-09-26 | Mendez; Alejandro | Composition for extending shelf life for fresh fruits and vegetables without the use of refrigeration |
| US6797300B2 (en) * | 1999-03-23 | 2004-09-28 | Alejandro Mendez | Composition for preserving fresh cut flowers, fresh fruits and vegetables without the use of refrigeration |
| US20050037116A1 (en) * | 1999-03-23 | 2005-02-17 | Alejandro Mendez | Synthetic solution for preserving fresh flowers, fruits, and vegetables without the use of refrigeration, and method of producing same |
| KR100314668B1 (en) * | 1999-05-26 | 2001-11-17 | 은종방 | Continuous extraction of pectin and hesperidin in tangerine peel |
| US6426362B1 (en) * | 1999-10-08 | 2002-07-30 | Galileo Laboratories, Inc. | Formulations of tocopherols and methods of making and using them |
| US20020006953A1 (en) * | 1999-11-05 | 2002-01-17 | Carla R. McGill | Modification of cholesterol concentrations with citus phytochemicals |
| WO2002026047A1 (en) * | 2000-09-25 | 2002-04-04 | Alejandro Mendez | Composition for preserving fruits and vegetables, method of making said composition, and method of using said composition without refrigeration |
| AU2001232182A1 (en) * | 2001-01-15 | 2002-07-24 | Kgk Synergize | Compositions and methods for regulating lipoproteins and hypercholesterolmia with limonoids flavonoids and tocotrienols |
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| CN103304610A (en) * | 2012-12-24 | 2013-09-18 | 李玉山 | Preparation process of methyl hesperidin |
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